X-Linked agammaglobulinemia (XLA) is a congenital immunodeficiency disease, characterized by the virtual absence of serum immunoglobulins of all classes, the inability to make antibodies and the absence of plasma cells from lymphoid tissues. Only males are afflicted with this disorder. Affected individuals have recurrent pyogenic identifying heterozygotes have been developed and no linkage to markers are known to be on the X chromosome. We have recently mapped the locus responsible for the XLA gene to the proximal long arm of the human X chromosome. Our studies using molecular linkage analysis on families with XLA indicate that the defect lies within the Xq21.3- Xq22 region. The two polymorphic probes which demonstrated genetic linkage to the disease locus are DXS3 and DX17 (named 19-2 and S21 respectively). Recombinant DNA libraries (pERT) enriched for DNA sequences map within the Xq21.3-Xq22 region, have recently been constructed and will serve as sources for generating X chromosome specific DNA markers. These markers will be used to expand the number of cloned DNA fragments for chromosome "walking" studies and restriction fragment length polymorphisms (RFLPs). Markers for RFLPs closely linked to the XLA locus will be developed to refine the mapping for use in carrier detection and act as starting points for identification and characterisation of structural aberrations in the disease gene locus. Ultimately, the work described here should lead to the identification of the defective gene and its putative transcript(s), and to better understanding of the molecular and cellular defects in XLA individuals.